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Saturated Fatty Acids Undergo Intracellular Crystallization and Activate the NLRP3 Inflammasome in Macrophages.

Arteriosclerosis, thrombosis, and vascular biology (2018-02-14)
Tadayoshi Karasawa, Akira Kawashima, Fumitake Usui-Kawanishi, Sachiko Watanabe, Hiroaki Kimura, Ryo Kamata, Koumei Shirasuna, Yutaro Koyama, Ayana Sato-Tomita, Takashi Matsuzaka, Hiroshi Tomoda, Sam-Yong Park, Naoya Shibayama, Hitoshi Shimano, Tadashi Kasahara, Masafumi Takahashi
ABSTRACT

Inflammation provoked by the imbalance of fatty acid composition, such as excess saturated fatty acids (SFAs), is implicated in the development of metabolic diseases. Recent investigations suggest the possible role of the NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3) inflammasome, which regulates IL-1β (interleukin 1β) release and leads to inflammation, in this process. Therefore, we investigated the underlying mechanism by which SFAs trigger NLRP3 inflammasome activation. The treatment with SFAs, such as palmitic acid and stearic acid, promoted IL-1β release in murine primary macrophages while treatment with oleic acid inhibited SFA-induced IL-1β release in a dose-dependent manner. Analyses using polarized light microscopy revealed that intracellular crystallization was provoked in SFA-treated macrophages. As well as IL-1β release, the intracellular crystallization and lysosomal dysfunction were inhibited in the presence of oleic acid. These results suggest that SFAs activate NLRP3 inflammasome through intracellular crystallization. Indeed, SFA-derived crystals activated NLRP3 inflammasome and subsequent IL-1β release via lysosomal dysfunction. Excess SFAs also induced crystallization and IL-1β release in vivo. Furthermore, SFA-derived crystals provoked acute inflammation, which was impaired in IL-1β-deficient mice. These findings demonstrate that excess SFAs cause intracellular crystallization and subsequent lysosomal dysfunction, leading to the activation of the NLRP3 inflammasome, and provide novel insights into the pathogenesis of metabolic diseases.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Bovine Serum Albumin, heat shock fraction, protease free, fatty acid free, essentially globulin free, pH 7, ≥98%
Sigma-Aldrich
Lipopolysaccharides from Escherichia coli O111:B4, γ-irradiated, BioXtra, suitable for cell culture
Triolein, European Pharmacopoeia (EP) Reference Standard
Tripalmitin, NIST® SRM® 1595